Honokiol Induces Autophagic Apoptosis in Neuroblastoma Cells through a P53-Dependent Pathway

2019 ◽  
Vol 47 (04) ◽  
pp. 895-912 ◽  
Author(s):  
Ming-Chung Lin ◽  
Yuan-Wen Lee ◽  
Yuan-Yun Tseng ◽  
Yung-Wei Lin ◽  
Jui-Tai Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Therapeutic Option ◽  
Neuroblastoma Cells ◽  
Cytochrome C Release ◽  
Dependent Pathway ◽  
Dependent Mechanism ◽  
Stimulation Of

In children, neuroblastomas are the most common and deadly solid tumor. Our previous studies showed that honokiol can cross the blood–brain barrier and kill neuroblastoma cells. In this study, we further evaluated if exposure to honokiol for short periods could induce autophagy and subsequent apoptosis of neuroblastoma cells and possible mechanisms. Exposure of neuroblastoma neuro-2a cells to honokiol for 24[Formula: see text]h induced morphological shrinkage and cell death. As to the mechanisms, honokiol consecutively induced cytochrome c release from mitochondria, caspase-3 activation, DNA fragmentation and cell apoptosis. Separately, honokiol time-dependently augmented the proportion of autophagic cells and the ratio of light chain 3 (LC3)-II/LC3-I. Pretreatment of neuro-2a cells with 3-methyladenine, an inhibitor of autophagy, attenuated honokiol-induced cell autophagy, caspase-3 activation, DNA damage and cell apoptosis. In contrast, stimulation of autophagy by rapamycin, an inducer of autophagy, significantly enhanced honokiol-induced cell apoptosis. Furthermore, honokiol-induced autophagic apoptosis was confirmed in neuroblastoma NB41A3 cells. Knocking down translation of p53 using RNA interference attenuated honokiol-induced autophagy and apoptosis in neuro-2a and NB41A3 cells. Taken together, this study showed that at early periods, honokiol can induce autophagic apoptosis of neuroblastoma cells through activating a p53-dependent mechanism. Consequently, honokiol has the potential to be a therapeutic option for neuroblastomas.

DNA damage-induced neural precursor cell apoptosis requires p53 and caspase 9 but neither Bax nor caspase 3

Development ◽  
2001 ◽  
Vol 128 (1) ◽  
pp. 137-146
Author(s):  
C. D'Sa-Eipper ◽  
J.R. Leonard ◽  
G. Putcha ◽  
T.S. Zheng ◽  
R.A. Flavell ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cell Apoptosis ◽  
Neuronal Apoptosis ◽  
Caspase 3 ◽  
Precursor Cell ◽  
Neural Precursor ◽  
Normal Brain ◽  
Neural Precursor Cell ◽  
Caspase 9

Programmed cell death (apoptosis) is critical for normal brain morphogenesis and may be triggered by neurotrophic factor deprivation or irreparable DNA damage. Members of the Bcl2 and caspase families regulate neuronal responsiveness to trophic factor withdrawal; however, their involvement in DNA damage-induced neuronal apoptosis is less clear. To define the molecular pathway regulating DNA damage-induced neural precursor cell apoptosis, we have examined the effects of drug and gamma-irradiation-induced DNA damage on telencephalic neural precursor cells derived from wild-type embryos and mice with targeted disruptions of apoptosis-associated genes. We found that DNA damage-induced neural precursor cell apoptosis, both in vitro and in vivo, was critically dependent on p53 and caspase 9, but neither Bax nor caspase 3 expression. Neural precursor cell apoptosis was also unaffected by targeted disruptions of Bclx and Bcl2, and unlike neurotrophic factor-deprivation-induced neuronal apoptosis, was not associated with a detectable loss of cytochrome c from mitochondria. The apoptotic pathway regulating DNA damage-induced neural precursor cell death is different from that required for normal brain morphogenesis, which involves both caspase 9 and caspase 3 but not p53, indicating that additional apoptotic stimuli regulate neural precursor cell numbers during telencephalic development.

scholarly journals Role for Caspase-Mediated Cleavage of Rad51 in Induction of Apoptosis by DNA Damage

1999 ◽  
Vol 19 (4) ◽  
pp. 2986-2997 ◽  
Author(s):  
YinYin Huang ◽  
Shuji Nakada ◽  
Takatoshi Ishiko ◽  
Taiju Utsugisawa ◽  
Rakesh Datta ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Mammalian Cells ◽  
Caspase 3 ◽  
Apoptotic Response ◽  
Cell Death Response ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis ◽  
Dependent Mechanism

ABSTRACT We report here that the Rad51 recombinase is cleaved in mammalian cells during the induction of apoptosis by ionizing radiation (IR) exposure. The results demonstrate that IR induces Rad51 cleavage by a caspase-dependent mechanism. Further support for involvement of caspases is provided by the finding that IR-induced proteolysis of Rad51 is inhibited by Ac-DEVD-CHO. In vitro studies show that Rad51 is cleaved by caspase 3 at a DVLD/N site. Stable expression of a Rad51 mutant in which the aspartic acid residues were mutated to alanines (AVLA/N) confirmed that the DVLD/N site is responsible for the cleavage of Rad51 in IR-induced apoptosis. The functional significance of Rad51 proteolysis is supported by the finding that, unlike intact Rad51, the N- and C-terminal cleavage products fail to exhibit recombinase activity. In cells, overexpression of the Rad51(D-A) mutant had no effect on activation of caspase 3 but did abrogate in part the apoptotic response to IR exposure. We conclude that proteolytic inactivation of Rad51 by a caspase-mediated mechanism contributes to the cell death response induced by DNA damage.

scholarly journals Young WI-38 human fibroblasts apoptosis after to staurosporine exposure: a preliminary assessment

2009 ◽  
Vol 15 (S3) ◽  
pp. 23-24
Author(s):  
F. Leal-Seabra ◽  
L. Matos ◽  
H. Almeida
Keyword(s):  
Cell Death ◽  
Cell Biology ◽  
Caspase 3 ◽  
Human Fibroblasts ◽  
Preliminary Assessment ◽  
Cytochrome C Release ◽  
Caspase Inhibition ◽  
Pathway Activation ◽  
General Inhibitor ◽  
Dependent Pathway

AbstractHuman fibroblasts cell culture is an important technique for the study of cell biology under various conditions, as exposure to apoptotic stimuli such as UV radiation or hydrogen peroxide administration or chemotherapeutic agent derivatives from staurosporine (STP). STP, isolated from Streptomyces staurospores, is a general inhibitor of protein kinases, and is commonly used to induce apoptosis in a variety of cell in cultures as tumor cell lines, lymphocytes, neurons and osteoblasts. The mechanism by which STP induce cell death is still unkown. Some studies refer that STP induced cell death courses with cytochrome c release, caspase-dependent pathway activation, especially caspase-3, and is inhibited by Bcl-2 overexpression. However cell death still occurs after caspase inhibition by z-VAD-fmk suggesting that caspase independent pathway is also activated.

scholarly journals Mechanisms of programmed cell death

2019 ◽  
Vol 6 (4) ◽  
pp. 156-158
Author(s):  
Abdu-Alhameed A Ali Azzwali ◽  
 Azab Elsayed Azab
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Nuclear Dna ◽  
Chromatin Condensation ◽  
Cell Shrinkage ◽  
Membrane Blebbing ◽  
Development And Aging ◽  
Nuclear Dna Fragmentation ◽  
Dependent Pathway

The present review aims to spotlight on the mechanisms and stages of programmed cell death. Apoptosis, known as programmed cell death, is a homeostatic mechanism that generally occurs during development and aging in order to keep cells in tissue. It can also act as a protective mechanism, for example, in immune response or if cells are damaged by toxin agents or diseases. In cancer treatment, drugs and irradiation used in chemotherapy leads to DNA damage, which results in triggering apoptosis through the p53 dependent pathway in cancer treatment, drugs and irradiation used in chemotherapy leads to DNA damage, which results in triggering apoptosis through the p53 dependent pathway. Corticosteroids can cause apoptotic death in a number of cells. A number of changes in cell morphology are related to the different stages of apoptosis, which includes nuclear DNA fragmentation, cell shrinkage, chromatin condensation, membrane blebbing, and the formation of apoptotic bodies. There are three pathways for apoptosis, the intrinsic (mitochondrial) and extrinsic (death receptor) are the two major paths that are interlinked and that can effect one another. Conclusion: It can be concluded that apoptosis is a homeostatic mechanism that generally occurs during development and aging in order to keep cells in tissue. Drugs and irradiation used in chemotherapy leads to DNA damage, which results in triggering apoptosis through the p53 dependent pathway. The apoptosis, stages are includes nuclear DNA fragmentation, cell shrinkage, chromatin condensation, membrane blebbing, and the formation of apoptotic bodies. There are three pathways for apoptosis.

Sensitization for γ-Irradiation-Induced Apoptosis by Smac.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3392-3392
Author(s):  
Stavros Giagkousiklidis ◽  
Hubert Kasperczyk ◽  
Meike Vogler ◽  
Klaus-Michael Debatin ◽  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Membrane Damage ◽  
Neuroblastoma Cells ◽  
Cellular Stress Response ◽  
Caspase Inhibitor ◽  
Cytochrome C Release ◽  
Γ Irradiation ◽  
Induced Apoptosis ◽  
First Time

Abstract Smac is released from mitochondria during the onset of apoptosis and promotes apoptosis via abrogating the binding of Inhibitor of Apoptosis Proteins (IAPs) to caspases. γ-irradiation is one of the most commonly used therapeutic approaches in clinical oncology, which triggers cell death in tumors via DNA and/or membrane damage. Since we recently found that Smac agonists sensitized even resistant tumors for apoptosis induced by death receptor ligation or anticancer drugs, we investigated the effect of Smac agonists on apoptosis following γ-irradiation in the present study. Here, we report for the first time that overexpression of mitochondrial or cytosolic Smac significantly increased radiosensitivity of various cancers. Transfection-enforced expression of Smac strongly enhanced apoptosis upon γ-irradiation in SH-EP neuroblastoma cells, which were resistant to g-irradiation in the absence of Smac. Importantly, Smac overexpression also reduced clonogenic tumor cell survival following γ-irradiation. Analysis of signaling pathways revealed that overexpression of Smac resulted in more rapid and more potent activation of caspase pathways, e.g caspase-2, -3,- 8, -9. The broad range caspase inhibitor zVAD.fmk abrogated apoptosis upon γ-irradiation indicating that apoptosis was mediated by caspases. In addition, overexpression of Smac promoted loss of mitochondrial membrane potential and cytochrome c release upon γ-irradiation. Interestingly, γ-irradiation-induced mitochondrial perturbations were blocked in the presence of the caspase inhibitor zVAD.fmk suggesting that caspase activity was required for mitochondrial alterations in response to γ-irradiation. Notably, cell cycle alterations and activation of NF-κB occured in a similar manner in vector control and Smac-transfected cells suggesting that Smac did not significantly alter the initial cellular stress response upon γ-irradiation. Importantly, Smac overexpression sensitized various tumor cell lines for γ-irradiation-induced apoptosis, indicating that the sensitization effect of Smac for γ-irradiation was not restricted to a particular cell type. By demonstrating that Smac can sensitize various tumor cells towards γ-irradiation-induced cell death, our findings provide for the first time evidence that Smac agonists may be a useful tool to enhance radiosensitivity in a variety of human cancers.

scholarly journals Hyperglycemia Enhances DNA Fragmentation after Transient Cerebral Ischemia

2001 ◽  
Vol 21 (5) ◽  
pp. 568-576 ◽  
Author(s):  
Ping-An Li ◽  
Ingrid Rasquinha ◽  
Qing Ping He ◽  
Bo K. Siesjö ◽  
Katalin Csiszár ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Cell Death ◽  
Cytochrome C ◽  
Dna Fragmentation ◽  
Caspase 3 ◽  
Cingulate Cortex ◽  
Tunel Staining ◽  
Dna Fragments ◽  
Cytochrome C Release ◽  
Klenow Polymerase

Previous histopathologic results have suggested that one mechanism whereby hyperglycemia (HG) leads to exaggerated ischemic damage involves fragmentation of DNA. DNA fragmentation in normoglycemia (NG) and HG rats subjected to 30 minutes of forebrain ischemia was studied by terminal deoxynucleotidyl transferase mediated DNA nick-labeling (TUNEL) staining, by pulse-field gel electrophoresis (PFGE), and by ligation-mediated polymerase chain reaction (LM-PCR). High molecular weight DNA fragments were detected by PFGE, whereas low molecular weight DNA fragments were detected using LM-PCR techniques. The LM-PCR procedure was performed on DNA from test samples with blunt (without Klenow polymerase) and 3′-recessed ends (with Klenow polymerase). In addition, cytochrome c release and caspase-3 activation were studied by immunocytochemistry. Results show that HG causes cytochrome c release, activates caspase-3, and exacerbates DNA fragments induced by ischemia. Thus, in HG rats, but not in control or NGs, TUNEL-stained cells were found in the cingulate cortex, neocortex, thalamus, and dorsolateral crest of the striatum, where neuronal death was observed by conventional histopathology, and where both cytosolic cytochrome c and active caspase-3 were detected by confocal microscopy. In the neocortex, both blunt-ended and stagger-ended fragments were detected in HG, but not in NG rats. Electron microscopy (EM) analysis was performed in the cingulate cortex, where numerous TUNEL-positive neurons were observed. Although DNA fragmentation was detected by TUNEL staining and electrophoresis techniques, EM analysis failed to indicate apoptotic cell death. It is concluded that HG triggers a cell death pathway and exacerbates DNA fragmentation induced by ischemia.

scholarly journals Co-involvement of the mitochondria and endoplasmic reticulum in cell death induced by the novel ertargeted protein HAP

2006 ◽  
Vol 11 (2) ◽  
Author(s):  
Hua Xu ◽  
Qing Zhou ◽  
Xin Liu ◽  
Yi-Peng Qi
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Membrane Potential ◽  
Hela Cells ◽  
Cell Apoptosis ◽  
Mitochondrial Membrane ◽  
Caspase 3 ◽  
Protein A ◽  
The Novel ◽  
Induce Cell Apoptosis

AbstractHAP (a homologue of the ASY/Nogo-B protein), a novel human apoptosis-inducing protein, was found to be identical to RTN3. In an earlier study, we demonstrated that HAP localized exclusively to the endoplasmic reticulum (ER) and that its overexpression could induce cell apoptosis via a depletion of endoplasmic reticulum (ER) Ca2+ stores. In this study, we show that overexpression of HAP causes the activation of caspase-12 and caspase-3. We still detected the collapse of mitochondrial membrane potential (Δωm) and the release of cytochrome c in HAP-overexpressing HeLa cells. All the results indicate that both the mitochondria and the ER are involved in apoptosis caused by HAP overexpression, and suggest that HAP overexpression may initiate an ER overload response (EOR) and bring about the downstream apoptotic events.

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